{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:21:16Z","timestamp":1791346876802,"version":"4.3.1"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,9,29]],"date-time":"2019-09-29T00:00:00Z","timestamp":1569715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT1066235"],"award-info":[{"award-number":["GNT1066235"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["FT130101648"],"award-info":[{"award-number":["FT130101648"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Ophthalmic Research Institute of Australia","award":["no grant number specified"],"award-info":[{"award-number":["no grant number specified"]}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["CNPq: 400167\/2016-6"],"award-info":[{"award-number":["CNPq: 400167\/2016-6"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Foundation for Support of Teaching, Research &amp; Assistance of the Clinical Hospital, Faculty of Medicine of Ribeira\u0303o Preto - University of Sa\u0303o Paulo","award":["FAEPA: 1901\/2017"],"award-info":[{"award-number":["FAEPA: 1901\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>When a person becomes infected with Toxoplasma gondii, ocular toxoplasmosis is the most common clinical presentation. The medical literature describes retinitis with surrounding hyperpigmentation secondary to proliferative changes in the retinal pigment epithelium, which is sufficiently characteristic that investigation often is not needed to make the diagnosis. We aimed to establish the frequency of \u201ctypical\u201d ocular toxoplasmosis and delineate its molecular basis. Among 263 patients presenting consecutively with ocular toxoplasmosis to Ribeir\u00e3o Preto General Hospital in Brazil, where T. gondii infection is endemic, 94.2% of 345 eyes had retinal hyperpigmentation. In ARPE-19 and primary human retinal pigment epithelial cell monolayers exposed to minimal numbers of T. gondii tachyzoites, the proliferation marker\u2013KI-67\u2013was increased in uninfected cells, which also were rendered more susceptible to infection. RT-qPCR and ELISA detected increased expression of vascular endothelial growth factor A (VEGF) and insulin-like growth factor (IGF)1, and decreased expression of thrombospondin (TSP)1 by infected cells. Blockade of VEGF and IGF1\u2014or supplementation of TSP1\u2014reversed the proliferation phenotype in uninfected cells. Our findings confirm that hyperpigmentation is a characteristic feature of retinitis in ocular toxoplasmosis, and demonstrate that T. gondii-infected human retinal pigment epithelial cells secrete VEGF and IGF1, and reduce production of TSP1, to promote proliferation of adjacent uninfected cells and create this disease-specific appearance.<\/jats:p>","DOI":"10.3390\/microorganisms7100405","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T05:58:33Z","timestamp":1569823113000},"page":"405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Molecular Basis of The Retinal Pigment Epithelial Changes That Characterize The Ocular Lesion in Toxoplasmosis"],"prefix":"10.3390","volume":"7","author":[{"given":"Shervi","family":"Lie","sequence":"first","affiliation":[{"name":"College of Medicine &amp; Public Health, Flinders University, Adelaide 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1rbara R.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"Arruda","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam M.","family":"Ashander","sequence":"additional","affiliation":[{"name":"College of Medicine &amp; Public Health, Flinders University, Adelaide 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-5747","authenticated-orcid":false,"given":"Jo\u00e3o M.","family":"Furtado","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4756-5493","authenticated-orcid":false,"given":"Justine R.","family":"Smith","sequence":"additional","affiliation":[{"name":"College of Medicine &amp; Public Health, Flinders University, Adelaide 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1442-9071.2012.02838.x","article-title":"Ocular toxoplasmosis II: Clinical features, pathology and management","volume":"41","author":"Butler","year":"2013","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1016\/S0140-6736(04)16412-X","article-title":"Toxoplasmosis","volume":"363","author":"Montoya","year":"2004","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/j.1442-9071.2012.02821.x","article-title":"Ocular toxoplasmosis I: Parasitology, epidemiology and public health","volume":"41","author":"Furtado","year":"2013","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_4","first-page":"1","article-title":"Ocular toxoplasmosis: A global reassessment. Part II: Disease manifestations and management","volume":"137","author":"Holland","year":"2004","journal-title":"Am. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000449169","article-title":"Recent developments in the diagnosis and treatment of ocular toxoplasmosis","volume":"57","author":"Ozgonul","year":"2017","journal-title":"Ophthalmic Res."},{"key":"ref_6","unstructured":"Kolb, H., Fernandez, E., and Nelson, R. (2011). The retinal pigment epithelium. Webvision: The Organization of the Retina and Visual System, University of Utah Health Sciences Center."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1001\/archopht.1976.03910030120009","article-title":"Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy","volume":"94","author":"Nicholson","year":"1976","journal-title":"Arch. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/0002-9394(88)90697-6","article-title":"Ocular toxoplasmosis in patients with the acquired immunodeficiency syndrome","volume":"106","author":"Holland","year":"1988","journal-title":"Am. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/S0161-6420(90)32412-0","article-title":"Toxoplasma gondii retinochoroiditis and optic neuritis in acquired immune deficiency syndrome. Report of a case","volume":"97","author":"Grossniklaus","year":"1990","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S0161-6420(83)80012-8","article-title":"Opportunistic toxoplasmic retinochoroiditis following chemotherapy for systemic lymphoma. A light and electron microscopic study","volume":"90","author":"Yeo","year":"1983","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1001\/archopht.1986.01050160127028","article-title":"Diffuse toxoplasmic retinochoroiditis in a patient with AIDS","volume":"104","author":"Parke","year":"1986","journal-title":"Arch. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1111\/j.1755-3768.2012.02531.x","article-title":"Spectral optical coherence tomography findings in patients with ocular toxoplasmosis and active satellite lesions (MINAS Report 1)","volume":"91","author":"Orefice","year":"2013","journal-title":"Acta Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00436-003-1031-2","article-title":"Ocular toxoplasmosis: The role of retinal pigment epithelium migration in infection","volume":"92","author":"Tedesco","year":"2004","journal-title":"Parasitol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1590\/0037-8682-0214-2017","article-title":"Prevalence and risk factors of toxoplasmosis among adults in a small Brazilian city","volume":"51","author":"Passos","year":"2018","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/exer.1996.0020","article-title":"ARPE-19, a human retinal pigment epithelial cell line with differentiated properties","volume":"62","author":"Dunn","year":"1996","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"708","DOI":"10.3389\/fimmu.2019.00708","article-title":"Immunological molecular responses of human retinal pigment epithelial cells to infection with Toxoplasma gondii","volume":"10","author":"Lie","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6856","DOI":"10.1167\/iovs.12-10384","article-title":"Migration of Toxoplasma gondii-infected dendritic cells across human retinal vascular endothelium","volume":"53","author":"Furtado","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1128\/EC.00150-09","article-title":"Phenotypic and gene expression changes among clonal type I strains of Toxoplasma gondii","volume":"8","author":"Khan","year":"2009","journal-title":"Eukaryot. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1128\/AAC.47.1.309-316.2003","article-title":"High-throughput growth assay for Toxoplasma gondii using yellow fluorescent protein","volume":"47","author":"Gubbels","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","first-page":"916","article-title":"Insulin-like growth factor-related genes, receptors, and binding proteins in cultured human retinal pigment epithelial cells","volume":"35","author":"Takagi","year":"1994","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/jcp.1041640219","article-title":"Vasculotropin\/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro","volume":"164","author":"Guerrin","year":"1995","journal-title":"J. Cell. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s00417-003-0828-0","article-title":"Role of growth factors and the wound healing response in age-related macular degeneration","volume":"242","author":"Schlingemann","year":"2004","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_23","first-page":"839","article-title":"Growth factor responsiveness of human retinal pigment epithelial cells","volume":"31","author":"Leschey","year":"1990","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12266","DOI":"10.14814\/phy2.12266","article-title":"Expression of pigment epithelium-derived factor and thrombospondin-1 regulate proliferation and migration of retinal pigment epithelial cells","volume":"3","author":"Farnoodian","year":"2015","journal-title":"Physiol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1111\/j.1462-5822.2008.01117.x","article-title":"Infection with Toxoplasma gondii results in dysregulation of the host cell cycle","volume":"10","author":"Molestina","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"811","DOI":"10.5301\/EJO.2011.6403","article-title":"Prevalence, clinical characteristics, and causes of vision loss in patients with ocular toxoplasmosis","volume":"21","author":"London","year":"2011","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S0161-6420(02)00990-9","article-title":"Ocular toxoplasmosis: Clinical features and prognosis of 154 patients","volume":"109","author":"Berendschot","year":"2002","journal-title":"Ophthalmology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cyto.2014.03.005","article-title":"Ocular cytokinome is linked to clinical characteristics in ocular toxoplasmosis","volume":"68","author":"Pfaff","year":"2014","journal-title":"Cytokine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1097\/IAE.0b013e3181dde70b","article-title":"Intraocular and serum levels of vascular endothelial growth factor in acute retinal necrosis and ocular toxoplasmosis","volume":"30","author":"Wiertz","year":"2010","journal-title":"Retina"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9356728","DOI":"10.1155\/2019\/9356728","article-title":"Immune mediator profile in aqueous humor differs in patients with primary acquired ocular toxoplasmosis and recurrent acute ocular toxoplasmosis","volume":"2019","author":"Thieme","year":"2019","journal-title":"Mediators Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1146\/annurev-micro-091014-104353","article-title":"Genetic mapping of pathogenesis determinants in Toxoplasma gondii","volume":"70","author":"Behnke","year":"2016","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1556\/030.64.2017.016","article-title":"Association between Toxoplasma gondii types and outcomes of human infection: A meta-analysis","volume":"64","author":"Xia","year":"2017","journal-title":"Acta Microbiol. Immunol. Hung."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1111\/j.1462-5822.2007.01093.x","article-title":"Toxoplasma gondii exploits UHRF1 and induces host cell cycle arrest at G2 to enable its proliferation","volume":"10","author":"Brunet","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.placenta.2009.07.002","article-title":"Apoptosis and S phase of the cell cycle in BeWo trophoblastic and HeLa cells are differentially modulated by Toxoplasma gondii strain types","volume":"30","author":"Angeloni","year":"2009","journal-title":"Placenta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.molbiopara.2008.11.014","article-title":"Induction of mitotic S-phase of host and neighboring cells by Toxoplasma gondii enhances parasite invasion","volume":"164","author":"Lavine","year":"2009","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.apjtm.2015.12.013","article-title":"Influence of Toxoplasma gondii on in vitro proliferation and apoptosis of hepatoma carcinoma H7402 cell","volume":"9","author":"Wang","year":"2016","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.mib.2015.04.003","article-title":"Toxoplasma\u2019s ways of manipulating the host transcriptome via secreted effectors","volume":"26","author":"Hakimi","year":"2015","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1111\/j.1462-5822.2005.00628.x","article-title":"The host cell transcription factor hypoxia-inducible factor 1 is required for Toxoplasma gondii growth and survival at physiological oxygen levels","volume":"8","author":"Spear","year":"2006","journal-title":"Cell. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fcimb.2019.00036","article-title":"The activin receptor, Activin-Like Kinase 4, mediates Toxoplasma gondii activation of hypoxia inducible factor-1","volume":"9","author":"Lis","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Koshy, A.A., Dietrich, H.K., Christian, D.A., Melehani, J.H., Shastri, A.J., Hunter, C.A., and Boothroyd, J.C. (2012). Toxoplasma co-opts host cells it does not invade. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002825"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20811","DOI":"10.1038\/srep20811","article-title":"Tracing amino acid exchange during host-pathogen interaction by combined stable-isotope time-resolved Raman spectral imaging","volume":"6","author":"Naemat","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1017\/S0031182015001973","article-title":"Effect of Toxoplasma gondii infection on the junctional complex of retinal pigment epithelial cells","volume":"143","author":"Nogueira","year":"2016","journal-title":"Parasitology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Song, H.B., Jun, H.O., Kim, J.H., Lee, Y.H., Choi, M.H., and Kim, J.H. (2017). Disruption of outer blood-retinal barrier by Toxoplasma gondii-infected monocytes is mediated by paracrinely activated FAK signaling. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175159"},{"key":"ref_44","first-page":"391","article-title":"Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype","volume":"36","author":"Grisanti","year":"1995","journal-title":"Invest. Ophthalmol. Vis. Sci."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/7\/10\/405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:25:52Z","timestamp":1760189152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/7\/10\/405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,29]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["microorganisms7100405"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms7100405","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,29]]}}}